NO322920B1 - Bicyclic vasopressin agonists - Google Patents

Abstract

Compounds according to general formula (1), and pharmaceutically acceptable salts thereof, wherein V is a covalent bond or NH, X is selected from CH2, O and N-alkyl, Z is either S or -CH=CH-, R<1 >and R<2 >are independently selected from H, F, Cl, Br and alkyl, R<3 >is selected from OH, O-alkyl and NR<4>R<5>, R<4 >and R<5 >are each independently H or alkyl, or together are -(CH2)q-, p is 0, 1, 2, 3 or 4, and q is 4 or 5, are new. They are agonists at the asopressin V2 receptor and are useful as antidiuretics and pro-coagulants.

Description

The present invention relates to a group of new chemical compounds that act as agonists for the peptide hormone vasopressin and pharmaceutical compositions containing these. They reduce urine excretion from the kidneys, and as such can be used for the production of pharmaceutical preparations for the treatment of certain human diseases characterized by polyuria, - control of urinary incontinence and various disorders associated with bleeding.

Vasopressin is a peptide hormone secreted by the posterior pituitary gland. It acts on the kidney so that it increases water retention and thus reduces urine output. Because of this, vasopressin is often referred to as an "antidiuretic hormone". It also acts on the vasculature or blood vessels, where it produces a hypertensive effect. The cell receptors that control or direct these two effects have been shown to be different. The antidiuretic action is controlled by the type-2 vasopressin receptor, commonly called the V2 receptor. Agents that can interact with the V2 receptor and activate it in the same way as vasopressin are called V2 receptor agonists (or simply "VV agonists). Such agents will have an antidiuretic effect. If these agents act selectively only with the V2 receptor and not with the other vasopressin receptor subtypes, they will not have vasopressin's hypertensive effect.This would be an important safety concern and would make such agents attractive for the treatment of human disease states characterized by polyuria (which here includes an agent for high urine production).

Vasopressin

Such an agent is in fact already in use in human therapy. Desmopressin (or [1-desamino, D-Arg<8>]vasopressin, Minirin™, DD A VP™) is a peptide analog of vasopressin that is a selective agonist at the V2 receptor. It is used, among other things, in the treatment of central diabetes insipidus, which is a condition due to insufficient release of vasopressin. Said agent is also used to control nocturnal enuresis and can also be used to control nocturia. However, desmopressin is not an ideal agent in all respects. Even the best syntheses currently known for the agent are very time-consuming, and desmopressin cannot be adapted to the most appropriate purification techniques, for example crystallization. Consequently, desmopressin is relatively expensive. It also has low oral bioavailability, and there is some variability in this parameter.

Desmopressin

Thus, in general, a need exists for a selective vasopressin V2 receptor agonist which is easy to prepare and purify, and which also has high and predictable oral bioavailability. Such properties will most likely be most easily achieved by means of a non-peptide compound. These considerations have led to a number of research groups investigating non-peptide vasopressin V2 agonists, and their results are for example described in the international patent applications WO97/22591, WO99/06403, WO99/06409, WO00/46224, WO00/46225, WO00 /46227 and WO00/46228. However, the connections described in said applications are far from ideal. In particular, they have poor oral bioavailability, probably due to the fact that they all have low solubility in aqueous solutions.

There is therefore a need for new connections without the above-mentioned disadvantages. Such compounds are provided in the present invention characterized by what appears from the attached claims.

The present invention provides compounds with improved solubility and bioavailability.

Besides its antidiuretic effects, desmopressin is also used to increase the concentration in the blood of the clotting proteins known as factor VIII and von Willebrand factor. In a clinical context, this means that desmopressin can be used in the treatment of haemophilia A and von Willebrand's disease. Similar applications will be possible with the non-peptide agonist according to the present invention.

SUMMARY OF THE INVENTION

As described herein, the present invention relates to a series of compounds which are non-peptide agonists for vasopressin and which are selective for the V2 receptor subtype. These compounds can be represented by the general formula 1

where:

V is a covalent bond or NH,

X is selected from CH 2 , O and N-(C 1 -C 6 )alkyl

Z is either S or -CH=CH-,

R<1> and R<2> are independently selected from H, F, Cl, Br and alkyl,

R3 is selected from OH, O-alkyl and NR<4>R<5>,

R<4> and R<5> are independently H or C1-C6 alkyl, or together

-(CH2)q-,

p is 0, 1, 2, 3 or 4, and

q is 4 or 5.

The present invention further includes pharmaceutical compositions which comprise said vasopressin agonists, and where these compositions are particularly useful in the treatment of central diabetes insipidus, nocturnal enuresis and nocturia.

DESCRIPTION OF THE INVENTION

The present invention includes N-acyl tetrahydroazepine derivatives defined by the general formula 1.

And where V in this formula represents an NH group or a covalent bond. X represents a methylene group (-CH2-), an oxygen atom (O) or N-(Ci-Ce)alkyl. Z is a sulfur atom (S) or a group -CH=CH-.

R<1> and R<2> are independently selected from H, F, Cl, Br and C1-C6 alkyl groups.

R<3> is selected from OH, O-alkyl and NR<4>R5.

R<4> and R<5> are independently selected from H and alkyl groups. Alternatively, they can together be -(CH2)q-, where q is 4 or 5, so that together with the nitrogen atom to which they are attached, they form a pyrrolidine or piperidine ring.

The number p can be 0, 1, 2, 3 or 4. When p is 0, there will be a covalent bond between V and the COR<3-> group. When p is 0 and V is a covalent bond, then there will be a single covalent bond between the two carbonyl groups.

The term "alkyl" refers to saturated hydrocarbon groups which can either be linear or branched, and can contain up to six carbon atoms, such as methyl, ethyl, propyl, isopropyl, w-butyl, sec-cer-butyl, isobutyl, tertiary-butyl, neopentyl and H-hexyl.

Certain compounds of the general formula 1 are capable of forming salts with acids or bases. Compounds containing, for example, a basic nitrogen atom can form addition salts with mineral acids or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, citric acid and benzoic acid. Compounds containing acidic groups can also form salts with bases. Examples of such salts include the sodium, potassium, calcium, triethylammonium and tetraethylammonium salts. Compounds that have both acidic and basic groups can also form internal salts (zwitterions). As far as these salts are pharmaceutically acceptable, they are included in the present invention.

In a preferred embodiment of the invention, the group Z is -CH=CH-.

In another preferred embodiment of the invention, X is equal to S.

In another preferred embodiment of the invention, X is a methylene group, CH2.

In another preferred embodiment of the invention, R<1> is a hydrogen atom, and R2 is a methyl group or a chlorine atom.

In another preferred embodiment of the invention, R<1> is a methyl group or a chlorine atom, and R<2> is a hydrogen atom.

In another preferred embodiment of the invention, R<3> is O-(Ci-C6)alkyl.

Particularly preferred compounds according to the present invention combine the properties indicated for these preferred embodiments.

Individual preferred compounds according to the invention include (but are not limited to) the following: 1-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro- lH-\ -benzazepine, l-(4-[N-(2-methoxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-\H-\ -benzazepine, l-( 4-[N-(2-hydroxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(5-methoxy- 5-oxopentanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1//-1-benzazepine, 1 -(4- [N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl] -3 -methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-hydroxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3,4, 5-tetrahydro-1H-1-benzazepine, l-(3-methyl-4-[N-(2-methylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(2-dimethylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4- [N-(2-Methoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylb enzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-(N-(2-amino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2)3)4 )5-tetrahydro-1H-1-benzazepine, 4-(3-chloro-4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl-5s6,7,8-tetrahydro-4//-thieno[ 3,2-6]azepine, 5-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl)-2,3,4,5 -tetrahydro-1,5-benzoxazepine, l-(4 -[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine, l-(4-[ N-(3-Methoxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3>4)5-tetrahydro- IH-1 -benzazepine, 1 -(4- [N-(3-ethoxy-3- oxopropanoyl)aminomethyl] -3 -methylbenzoyl)-2,3,4,5-tetrahydro- \ H- 1 -benzazepine, 1 -(4- [N-(3-hydroxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl )-2,3,4,5-tetrahydro-1 H-1 -benzazepine, 1 -(4-[N-(4-hydroxy-4-oxobutanoyl)aminomethyl] -3-methylbenzoyl)-2,3,4, 5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(5-hydroxy-5-oxobutanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(3-methoxy-3- oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1 -benzazepine, l-(4-rN,-ethoxycarbonylcarbamoyl)aminomethyl3-3-methylbenzoyl)-2,3,4, 5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-2-methylbenzoyl-2,3,4,5-tetrahydro-1Jf-1-benzazepine , 1-(4-{N-(2-isopropoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3s4,5-tetrahydro-1 H-1 -benzazepine, 1 -(4- [N-(2 -f-butoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(3-chloro-4-[N-(2- Dimethylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(3-methyl-4-[N-(2-(l-piperidino)-2 -oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(3-methyl-4-|N-(2-(l-pyrrolidino)-2-oxoethylcarbamo 2 ,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(3-ethoxy-3-oxopropylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro -1//-1-benzazepine, and 1-(4-[N-(3-hydroxy-3-oxopropylcarbamoyl)aminomethyl]-3-methylbenzoyl )-2,3,4,5-tetrahydro-\H-\-benzazepine.

The compounds according to the present invention can be prepared using methods which are known per se. The compounds of the general formula 1 can be considered to be composed of three linked fragments (A-C).

These three fragments will generally be prepared separately and then assembled at a later stage of synthesis. In certain cases, certain groups (especially R<3> and X) will be incompatible with such a composition and will require the use of protecting groups. Such protecting groups are well known in organic chemistry (see, for example, "Protective Groups in Organic Synthesis", T.W. Greene, Wiley-Interscience, 1981). Special groups that will require protection are amines (protected as amides or carbamates) and carboxylic acids (protected as esters). In the subsequent discussion and description, it is understood that such protective groups are present when this is necessary.

Fragments A, B and C can be combined into compounds of formula 1 using two strategies. In the first, fragments A and B will be joined to a fragment corresponding to AB, which is then combined with fragment C. In the second, fragments B and C will be joined to a fragment corresponding to BC, which is then combined with fragment A. The synthesis which involves the condensation of fragment A with B, and that which involves the condensation of fragment B with C, will be the same regardless of which strategy is used.

Formation of fragment AB

The type of reaction used to form the A-B bond will depend on the identity of V.

V is covalent bond.

Here {A} and {B} represent substructures of fragments A and B respectively. The formation of amides by a reaction between acid chlorides and primary amines is well known. Typically, the amine and acid chloride will be formed in an aprotic solvent, for example dichloromethane or dimethylformamide, in the presence of a tertiary amine such as triethylamine.

V = NH

The preparation of urea compounds by a reaction between an isocyanate and a primary amine is also well known. Usually the amine and the isocyanate will be mixed in an aprotic solvent such as dichloromethane or dimethylformamide. The presence of a tertiary amine such as triethylamine may be beneficial, but is not usually necessary.

Formation of fragment BC

Formation of the amide bond between fragments B and C can be most easily achieved by allowing the acid chloride corresponding to fragment B to react with the secondary amine that is part of the azepine ring in fragment C. The reaction can take place in an aprotic solvent in the presence of a tertiary amine base. Depending on the exact type of the two fragments, the reaction will require more or less time to achieve a satisfactory yield of product. Alternatively, the carboxylic acid corresponding to fragment B can be condensed with the azepine using one of the many reagents well known in organic chemistry to carry out reactions that form such amide bonds.

In general, the following intermediates will be necessary for the synthesis of the compounds according to the present invention

i) For fragment A

Acid chlorides are well known. Many acid chlorides have been described and are commercially available. If the required acid chloride is not a known compound, then it can usually be synthesized in a single step from the corresponding carboxylic acid. Isocyanates are also well known. In general, they can be prepared from the corresponding primary amine by reaction with phosgene or a corresponding reagent.

ii) For fragment B

Because the primary amine and acid chloride groups are incompatible, they must be developed separately and protected. The acid chloride can be prepared from the corresponding carboxylic acid, preferably protected as its methyl ester. The primary amine can be prepared from the corresponding nitrile (by reduction) or the alcohol (by replacement with a nitrogen nucleophile). The best method will depend on the type of the substituents R 1 and R ?.

iii) For fragment C

Condensed azepines of this type can be prepared using methods described in the literature.

The present invention further includes pharmaceutical compositions which comprise at least one compound according to the preceding description as an active ingredient. The composition may also include another pharmacological agent, for example as a spasmolytic agent or as a potassium channel blocker, and these agents are medically well known for the relief of bladder dysfunction. It is preferred that the composition contains only one active ingredient. The composition will also be able to include diluents selected from binders, bulking agents, dispersing agents, solvents, stabilizing agents and the like, and where such diluents and additives are well known.

Which diluents or additives are used will depend on the type of preparation and intended areas of application, which in turn will depend on the intended route of administration. Administration may be oral, transmucosal (such as sublingual, buccal, intranasal, vaginal and rectal), transdermal or by injection (such as subcutaneous, intramuscular or intravenous). Oral administration is generally preferred. For oral administration, the preparation will usually be a tablet or a capsule. Other preparation types include dry powders, solutions, suspensions, suppositories and the like.

In a further aspect, the present invention relates to use for preparing pharmaceutical preparations to treat or control certain human physiological dysfunctions. These preparations contain a compound as indicated in the preceding description, as an active ingredient. The compounds act in such a way that they reduce urinary excretion, so that the method according to the present invention can be used in all conditions where elevated or too strong urinary excretion is a contributing factor. The compounds will also increase the production of the blood clotting proteins known as factor VIII and von Willebrand factor, so they can also be used in the treatment of bleeding disorders or diseases.

In a preferred embodiment, the condition being treated is diabetes insipidus. This condition is caused by the body being unable to produce and secrete physiologically active vasopressin, with the result that water absorption in the body is greatly reduced and large volumes of urine are produced.

In another preferred embodiment, the condition being treated is nocturnal enuresis. This condition is defined by an emptying of the urinary bladder while the patient or individual sleeps. This condition occurs mainly in children, and a number of factors are involved in its etiology.

In another preferred embodiment, nocturia is the condition being treated. This condition is defined as the production of so much urine during the night that the individual wakes up and has to empty the bladder. Again, this condition can be caused by a number of different factors.

In another preferred embodiment, incontinence is the condition being treated. This condition is characterized in part by a reduced bladder capacity and control, so that an involuntary urination or urination occurs, if the urinary bladder is not emptied relatively often. Incontinence can be divided into two conditions, stress incontinence and urge incontinence. It is assumed that a number of etiological factors are involved in these conditions. Treatment according to the present invention is particularly useful for delaying the need to empty the urinary bladder ("voiding postponement"), so that the incontinent patient or individual can achieve a dry period of a couple of hours (for example up to four hours). Such treatment can also be beneficial for a non-continent population, for example for people who have to be present at very long meetings.

In another preferred condition, hemophilia A or von Willebrand disease is the condition being treated. These are conditions where factor VIII or von Willebrand factor production is reduced, and the individual suffers from prolonged bleeding.

In another preferred embodiment, the composition according to the invention will be administered before surgical intervention (this includes bowel operations), in order to increase the blood's coagulation ability and thereby reduce blood loss after or during the operation.

The administration of compositions will usually take place under the supervision of a physician. The doctor will be able to determine the amount of the composition to be administered and the dosage regimen, taking into account the patient's physical condition and the therapeutic goals. For an adult diabetes insipidus patient, a typical dose will vary from 50 mg to 1 g of the active compound per day, taken as a single tablet or up to four tablets during the day. For routes of administration other than oral, the amount of compound may be reduced, as such non-oral routes tend to be more effective in getting the therapeutic agents into systemic circulation. For the treatment of hemophilia A and von Willebrand's disease, the required amount of the compound will be higher than for the treatment of diabetes insipidus.

The foregoing general description will now be further illustrated by means of a number of non-limiting examples.

EXAMPLES

Abbreviations

The following abbreviations are used in the following examples.

AIBN Azo-6w-(isobutyronitrile)

BOC /e/7-Butyloxycarbonyl

(BOC)20 Di-tert-butyl dicarbonate

DIEA Diisopropylethylamine

DMF Dimethylformamide

EtOAc Ethyl acetate

IPA Isopropanol

M.S. Mass spectrometry

NBS N-Bromosuccinimide

NMR Nuclear magnetic resonance spectrometry

pet.eter Petroleum ether, the part that codes between 60 and 80°C

PyBroP® Bromotris(pyrrolidine)phofonium hexafluorophosphate

THF Tetrahydrofuran

WSCDI Water soluble carbodiimide

Production of intermediate products

Reagents corresponding to fragments A and C are commercially available, or can be prepared by published syntheses, except as detailed in the specific examples.

Reagents corresponding to fragment B were prepared as detailed below.

Example A

4-( ferf- butyloxycarbonvlaminomethvn- 3- chlorobenzoic acid).

Eel. Methyl 4- bromomethyl- 3- chlorobenzoate

To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in 50 mL of carbon tetrachloride was added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol ). The mixture was stirred at reflux for 18 hours. It was then cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent EtOAc:petroleum ether 0:100 to 5:95); yield 5.96 g (84%).

A2. 4-(ferr-butyloxycarbonylaminomethyl') 3-chlorobenzoic acid

To a saturated solution of ammonia in 170 ml of ethanol was added methyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was triturated with diethyl ether and the resulting white crystals were filtered off and washed with more diethyl ether. A solution of this solid product in 100 mL of water was added to solutions of (BOC) 2 O (5.0 g, 23.0 mmol) in 100 mL of dioxane and sodium hydroxide (1.86 g, 46.0 mmol) in 100 mL of water . The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/IPA. The organic layer was washed with water, dried over magnesium sulfate and concentrated in vacuo to give a white solid; yield 2.8 g (67%).

Example B

4- cyano- 3- methylbenzoic acid

A solution of 4-bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol) in 100 ml of THF was added dropwise at -78°C in a nitrogen atmosphere to a 2.5 M solution of «-butyllithium (4.48 ml, 11.2 mmol). The mixture was stirred at -78°C for 1 hour and poured over 5 g of solid carbon dioxide in 50 ml of THF. The mixture was allowed to warm to room temperature. 200 ml of water was added and the mixture was extracted 3 times with diethyl ether. The aqueous layer was acidified by adding concentrated HCl and then extracted 3 times with chloroform. The combined chloroform extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give a white solid; yield 1.2 6 (73%).

Example C

4- cvano- 2- methylbenzoic acid

4-Bromo-3-methylbenzonitrile (2.0 g, 10.2 mmol) was reacted using the procedure of Example B to give a yellow solid which was triturated with hexane and filtered; yield 0.96 g (59%). Example D 4-(ferr-butyloxycarbonvlaminomervO-2-lfluorobenzoic acid

Dr. 2-fluoro-4-methylbenzoic acid

4-Bromo-3-fluorotoluene (8.33 g, 44.07 mmol) was reacted using the procedure of Example B to give a white solid; 4.89 g (72%).

D2. Methyl 2-fluoro-4-methylbenzoate

To a solution of 2-fluoro-4-methylbenzoic acid from Example D1 (6.04 g, 39.18 mmol) in 80 mL of toluene was added thionyl chloride (6.5 mL, 89.11 mmol). The mixture was refluxed for 2.5 hours, cooled and concentrated in vacuo. The residue was dissolved in 50 ml of dichloromethane and 50 ml of methanol was added. The mixture was stirred at room temperature for 2.5 hours and then concentrated in vacuo. The residue was dissolved in 100 mL of dichloromethane, washed with saturated sodium bicarbonate solution and brine, then dried over magnesium sulfate and concentrated in vacuo to give a pale brown solid; yield 5.07 g (77%).

D3. Methyl 4- frommethovl- 2- fluorobenzoate

Methyl 2-fluoro-4-methylbenzoate from Example D2 (5.07 g, 30.16 mmol) was reacted using the procedure of Example A1. The product was purified by flash chromatography on silica (eluent ethyl acetate.petroleum ether 20:80); yield 5.9 g (80%).

D4. 4-( ?gr -butyloxycarbonylaminomethvn-2-fluorobenzoic acid Methyl 4-bromomethyl-2-fluorobenzoate from Example D3 (5.9 g, 24.13 mmol) was reacted following the procedure from Example A2. The product was recrystallized from dioxane/petroleum ether , giving white crystals; yield 2.46 g (38%). The compounds corresponding to fragments A, B and C were combined into the specific examples detailed below.

Example 1

l- f4-[ N- f4- methoxysv- 4- oxobutanovennamtDometvll- 3- mer\ rlbepzovn- 2. 3. 4. 5-tetrahydro- l//- l- benzazepine

1 A. 1 -(" 4- cvano- 3- metvlbenzovlV2. 3. 4. 5- tetrahvdro- 1 H - 1 - benzazepine A solution of 2,3,4,5-tetrahydro-\ H-\-benzazepine (0 .80 g, 5.44 mmol) in 40 ml of dichloromethane was added 4-cyano-3-methylbenzoic acid from example B (0.96 g, 5.95 mmol), triethylamine (0.76 g, 5.44 mmol), 4-(dimethylamino)pyridine (0.66 g, 5.44 mmol) and WSCDI (2.17 g, 10.88 mmol). The mixture was refluxed for 18 h, cooled and evaporated in vacuo. The residue was partitioned between ethyl acetate and 1 M KHSO*. The organic layer was washed with saturated sodium bicarbonate solution and then with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent ethyl acetate r petroleum ether 30:70); yield 1.10 g (70%). ;IB. 1 - f4-raminometvn- 3- methylbenzovlV2. 3. 4. 5- tetrahydro- l//- l - benzazepine hydrochloride ; A degassed solution of the cyanobenzoylbenzazepine from Example IA (1.10 g, 3, 79 mmol) in 40 ml of methanol was added concentrated hydrochloric acid (0.98 ml, 11.3 mmol) and 0.80 g of 10% palladium on carbon. Hydrogen gas was bubbled through the mixture for 5 hours at room temperature. The catalyst was removed by filtration through a cake of celite and the filtrate was evaporated in vacuo to give the product as the HCl salt; yield 1.23 g (98%). IC. 1 - f 4- rN- f4- methoxy- 4- oxobutanovenaminomethvn- 3 - metvlbenzovD- 2. 3. 4. 5-tetrahydro- 1 H - 1 - benzazepine; A solution of the amine from Example IB (0.10 g, 0 .30 mmol) in 10 mL of dichloromethane was added triethylamine (0.061 mL, 0.90 mmol) and 3-carbomethoxypropionyl chloride (0.046 g, 0.30 mmol). The mixture was stirred at room temperature for 18 h and then washed 3 times with 1 M KHSO 4 , water and brine, dried over sodium sulfate and concentrated in vacuo to a white solid; yield 0.10 g (81%). ;<!>H NMR: δ 1.40-1.60 (1H, m), 1.84-2.20 (3H, m), 2.15 (3H, s), 2.40-2.54 (2H, m), 2.58-2.92 (4H, m), 2.94-3.10 (1H, m), 3.65 (3H, s), 4.30 ( 2H, d, J = 5.6 Hz), 4.99 (1H, d, J = 12.9 Hz), 5.90 (1H, s), 6.62 (1H, d, J = 7.9 Hz), 6, 78-6.96 (3H, m), 7.00-7.16 (2H, m), 7.21 (1H, m) ppm. ;M.S.: calculated m/e = 408; found [M+H]<+> = 409. ;Example 2 ;1-( 4-[ N- 2- methoxy- 2- oxoethanol) aminomethyl- 3- methylbenzoyl- 2, 3. 4. 5-tetrahydro- lJ/ - l-benzazepine;;The amine hydrochloride from Example IB (0.10 g, 0.30 mmol) was reacted with methyloxalyl chloride (0.037 g, 0.30 mmol) by the procedure of Example 1C to give a white solid; yield 0.085 g (76%). ;'HNMR: δ 1.48-1.70 (1H, m), 1.96-2.16 (3H, m), 2.26 (3H, s), 2.78-3.18 (3H, m), 3.98 (3H, s), 4.50 (2H, d, J = 6.8 Hz), 5.08 (1H, d, J = 12.7 Hz), 6.72 (1H, d, J = 7.6 Hz), 6.88-7.06 (3H, m), 7.18 (1H, t, J = 7.6 Hz), 7.22-7.36 (2H, m ) ppm. ;M.S.: calculated m/e = 380; found [M+H]<+> = 381. ;Example 3 ;1- f4- fN-( 2- hydroxy- 2- oxoethanovl) aminomethyl- 3- methylbenzovl)- 2. 3. 4<5-tetrahydro- ljy- l-benzazepine ;;To a solution of the methyl ester from Example 2 (0.045 g, 0.118 mmol) in 10 mL THF and 5 mL water was added lithium hydroxide monohydrate (0.010 g, 0.23 mmol). The mixture was stirred at room temperature for 2 h, acidified to pH 1 by adding 1 M HCl and then extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to a white solid; yield 0.034 g (76%). ;<!>HNMR: δ 1.40-1.62 (1H, m), 1.84-2.24 (3H, s), 2.17 (3H, s), 2.70-3.10 ( 3H, m), 4.40 (2H, d, J = 5.9 Hz), 4.99 (1H, d, J = 12.9 Hz), 6.63 (1H, d, J = 7.6 Hz), 6.80-6.98 (3H, m), 7.02-7.28 (3H, m), 7.38 (1H, br s) ppm. ;M.S.: calculated m/e = 366; found [M+H]<+> = 367. ;Example 4 ;1-( 4- fN-( 5- methoxysv- 5- oxopentanovlaminomervH- 3- mervlbenzovl)- 2, 3. 4. 5-tetrahydro- l/ f - l-benzazepine;;The amine hydrochloride from Example IB (0.10 g, 0.30 mmol) was reacted with methyl 4-(chloroformyl)butyrate (0.050 g, 0.30 mmol) as indicated in Example 1C, and this gave a white solid; 0.061 g (48%). ;1H NMR: δ 1.42-1.62 (1H, m), 1.84-2.28 (8H, m), 2.30-2.50 (4H, m), 2.70-2.94 (2H, m), 2.96-3.12 (1H, m), 3.65 (3H, s), 4.31 (2H, d, J = 5.3 Hz), 4.99 (1H, d, J = 13.9 Hz), 5.75 (1H, br s), 6.63 (1H, d, J = 7.6 Hz), 6 .78-6.98 (3H, m), 7.02-7.16 (2H, m), 7.21 (1H, d, J = 6.6 Hz) ppm. ;M.S.: calculated m/e = 422; found [M+H]<+> = 423. ;Example 5 ;1- f4-[ N-( 2- ethoxv- 2- oxoethylcarbamovaminomethyl- 3- mervIbenzovn- 2, 3, 4, 5-tetrahydro- li/ - l-benzazepine ;;To a solution of the amine from example IB (0.10 g, 0.30 mmol) in 10 ml of dichloromethane was added triethylamine (0.061 ml, 0.90 mmol) and ethyl isocyanate acetate (0.059 g, 0.45 mmol) ).The mixture was stirred room temperature for 18 h and then washed with 3 times with 1 M KHSO 4 , water and brine, dried over magnesium sulfate and concentrated in vacuo to a white solid; yield 0.10 g (81%). ;'H NMR: δ 1.18 (3H, t, J = 7.3 Hz), 1.38-1.55 (1H, m), 1.80-2.10 (3H, m), 1, 95 (3H, s), 2.60-2.98 (3H, m), 3.84 (2H, s), 4.04 (2H, s), 4.07 (2H, q, J = 7, 3 Hz), 4.87-4.92 (1H, m), 5.73 (2H, br s), 6.50 (1H, d, J = 7.3 Hz), 6.63-6.97 (5H, m), 7.11 (1H, d, J = 7.3 Hz) ppm. ;M.S.: calculated m/e = 423; found [M+H]<+> = 424. ;Example 6 ;1- f4-[ N-( carboxymethylcarbamovaminomethyl-3- merylbenzoyl)- 2. 3, 4, 5-tetrahydro-1-g-1-benzazepine ;; To a solution of the ethyl ester from Example 5 (0.050 g, 0.10 mmol) in 20 mL THF and 5 mL water was added lithium hydroxide monohydrate (0.020 g, 0.45 mmol). The mixture was then stirred at room temperature for 4 hours. It was then concentrated in vacuo and the residue was diluted with water and then washed with diethyl ether. The aqueous layer was acidified to pH 1 by adding 1 M HCl and the layer was then extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to a white solid; yield 0.046 g (99%). ;'H NMR: δ 1.30-1.50 (1H, m), 1.75-2.05 (3H, m), 1.94 (3H, s), 2.60-2.98 (3H , m), 3.59 (2H, br s), 4.01 (2H, br s), 4.80-4.85 (1H, m), 6.05 (2H, br s), 6.53 (1H, d, J = 7.2 Hz), 6.75-6.99 (5H, m), 7.11 (1H, d, J = 7.2 Hz) ppm. ;M.S.: calculated m/e = 395; found [M+H]<+> = 396. ;Example 7 ;1- f4-[ N-(2-methylamino-2- oxoethylcarbamol) aminomethyl- 3- methylbenzovn-2, 3, 4, 5- tetrahydrol/ M-benzazepine ;;A solution of the carboxylic acid from Example 6 (0.10 g, 0.25 mmol) in 25 mL of dichloromethane was added DIEA (0.221 mL, 1.26 mmol) and PyBroP (0.129 g, 0.278 mmol). The mixture was stirred at room temperature for 10 minutes and then methylamine hydrochloride (0.085 g, 1.26 mmol) was added. Stirring was then continued for a further 3 hours. The mixture was then washed 3 times with 1 H KHSO 4 , 3 times with a saturated sodium bicarbonate solution and then with a brine solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent dichloromethane:methanol 96:4) to give a white solid; yield 0.018 g (17%). ;'H NMR: δ 1.40-1.60 (1H, m), 1.80-2.00 (2H, m), 2.00-2.20 (3H, s), 2.60 (3H , d, J = 4.0 Hz), 2.65-3.05 (3H, m), 3.60 (2H, d, J = 4.0 Hz), 4.15 (2H, d, J = 4.0 Hz), 4.90-5.00 (1H, m), 6.10-6.30 (2H, m), 6.60 (1H, d, J = 8.0 Hz), 6, 70-7.20 (8H, m) ppm. ;M.S.: calculated m/e = 408; found [M+H]<+> = 409. ;Example 8 *

1- f4- fN- f2- dimervlamino- 2- oxoethylcarbamol) aminomethyl- 3- methylbenzovn-2. 3. 4. 5- tetrah. vdro- lff- l- benzazepine

The carboxylic acid from Example 6 (0.07 g, 0.18 mmol) was reacted with dimethylamine hydrochloride (0.072 g, 0.88 mmol) using the procedure outlined in Example 7. The product was purified by flash chromatography on silica (eluent chloroform:methanol :acetic acid 98:1:1), and this gave a white solid; yield 0.08 g (11%).

1 H NMR: δ 1.39-1.50 (1H, m), 1.86-2.10 (3H, m), 2.07 (3H, s), 2.57 (2H, s), 2 .60-3.00 (3H, m), 2.85 (3H, s), 3.95 (2H, d, J = 4.0 Hz), 4.16 (2H, d, J = 5.6 Hz), 4.90-5.00 (1H, m), 5.74 (1H, br s), 6.11 (1H, br s), 6.54 (1H, d, J = 7.6 Hz ), 6.78-7.18 (6H, m) ppm.

M.S.: calculated m/e = 422; found [M+H]<+> = 423.

Example 9

l-( 4- fN- r2- methoxysv- 2- oxoetvlcarbamovaminometvll- 3- metvlbeDzovlU2. 3. 4. 5-tetrahvdro- l/ f- 1 - benzazepine

A solution of the carboxylic acid from Example 6 (0.080 g, 0.20 mmol) in a nitrogen atmosphere in 24 ml of dichloromethane was added at 0°C with 20 µl of DMF and oxalyl chloride (31 mg, 0.24 mmol). The mixture was stirred at 0°C to room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in 4 ml of methanol and 16 ml of dichloromethane, after which the mixture was stirred at room temperature for 16 hours. It was then washed 3 times with 1 M KHSO 4 , 3 times with a saturated sodium bicarbonate solution and then with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent dichloromethane:methanol 96:4) to give a white solid; yield 0.049 g (60%).

<]>H NMR: δ 1.38-1.50 (1H, m), 1.80-2.00 (3H, m), 2.00 (3H, s), 2.60-3.00 ( 3H, m), 3.64 (3H, s), 3.90 (2H, s), 4.10 (2H, s), 4.85-4.95 (1H, m), 6.52 (1H , d, J = 7.2 Hz), 6.67-7.02 (7H, m), 7.13 (1H, d, J = 6.2 Hz) ppm.

M.S.: calculated m/e = 409; found [M+H]<+> = 410.

Example 10

l-( 4-[ N-( 2- amino- 2- oxoethylcarbamovaminomethyl I- 3- methylbenzovn- 2. 3, 4, S-tetrahydro- li/- l- benzazepine

To a solution of the carboxylic acid from Example 6 (0.10 g, 0.25 mmol) in 20 mL of dichloromethane was added hydroxybenzotriazole (34 mg, 0.25 mmol) and WSCDI (51 mg, 0.25 mmol). The mixture was then stirred at room temperature for 10 minutes. 0.5 ml of ammonia 880 was then added and stirring continued for a further 16 hours. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica (eluent ethyl acetate) to give a white solid; yield 0.008 g (8%).

1H NMR: δ 1.40-1.76 (2H, m), 1.84-2.16 (2H, m), 2.29 (3H, s), 2.66-3.10 (3H, m), 3.95 (2H, s), 4.56 (2H, s), 4.99 (1H, d, J = 13.9 Hz), 5.59 (1H, br s), 6.63 (1H, d, J = 7.9 Hz), 6.80-6.98 (3H, m), 7.00-7.12 (2H, m), 7.20 (1H, d, J = 7 .3 Hz) ppm.

M.S.: calculated m/e = 394; found [M+H]<+> = 395.

Example 11

4- f4- fN-( 4- methoxysv- 4- oxobutanovItaminometvll- 3- chlorobenzovit- 5. 6. 7. 8-tetrahdro- 4i/- thienof3. 2- Ålazepine

11A. 4- f4-[ N- ffer/- butvloxvcarbonvnaniinometvl1- 3>chlorobenzovlVS. 6. 7. 8-tetrahydro-4//- thienof3. 2- f) 1azepine hydrochloride

The carboxylic acid from A2 (0.60 g, 2.10 mmol) was reacted with 5,6,7,8-tetrahydro-4/- thieno[3,2-6]azepine (0.28 g, 1.80 mmol ) according to the method from example IA. The product was purified by flash chromatography on silica (eluent ethyl acetate:petroleum ether 40:60) and this gave a yellow solid.

UB. 4- f4- raminometvn- 3- chlorobenzovlV5. 6. 7. 8- tetrahydro- 4//- thienor3. 2-elazepine hydrochloride

The BOC amine from 1 IA was dissolved in 30 mL of 4 N HCl/dioxane. The mixture was stirred at room temperature for 40 min and then concentrated in vacuo to give a pale brown solid; yield 0.41 g (63% for 2 steps).

11C. 4-( 4- rN-( f4- methoxy- 4- oxobutanoyl) aminomethvn- 3- chlorobenzoyl)- 5. 6. 7. 8-tetrahdro- 4//- thienof3. 2- 61azepine

To a solution of the amine from Example 11B (0.032 g, 0.08 mmol) in 10 mL of dichloromethane was added triethylamine (0.025 mL, 0.18 mmol) and 3-carbomethoxypropionyl chloride (0.014 g, 0.08 mmol). The mixture was stirred at room temperature for 18 hours and then washed 3 times with 1 M KHSO 4 , water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluent ethyl acetate/petroleum ether 50:50-90:10); yield 0.022 g (56%).

<1>R NMR: δ 1.70-1.86 (3H, m), 1.96-2.08 (2H, m), 2.44-2.56 (2H, m), 2.60- 2.72 (2H, m), 2.86-2.98 (2H, m), 3.67 (3H, s), 3.85 (1H, br s), 4.44 (2H, d, J = 5.9 Hz), 6.18 (1H, d, J = 5.3 Hz), 6.28 (1H, br s), 6.68 (1H, d, J = 5.3 Hz), 7 .03 (1H, d\ J = 7.6 Hz), 7.15 (1H, d, J = 7.6 Hz) ppm.

M.S.: calculated m/e = 434; found [M+H]<+> = 435.

Examples 12 - 28

The following compounds were prepared by methods analogous to those described above

Selected 'H NMR data:

a 1.17 (6H, d, J = 6.3 Hz), 1.20-1.24 (1H, m), 1.80-2.10 (3H, m), 2.00 (3H, s ),

2.60-3.00 (3H, m), 3.85 (2H, d, J = 5.3 Hz), 4.10 (2H, d, J = 4.9 Hz), 4.82-4 .85 (1H, m), 4.96 (1H, sept, J = 6.2 Hz), 5.33 (1H, t, J = 5.2 Hz), 5.43 (1H, t, J = 4.9 Hz), 6.52 (1H, d, J = 7.6 Hz) ppm.

b 1.38-1.42 (1H, m), 1.38 (9H, s), 1.78-2.10 (3H, m), 1.97 (3H, s), 2.60-3 ,00

(3H, m), 3.78 (2H, s), 4.07 (2H, s), 4.89-4.94 (1H, m), 5.50 (2H, br s), 6.51 (1H, d, J = 7.9 Hz), 6.64-6.98 (5H, m), 7.12 (1H, d, J = 7.7 Hz) ppm.

c 1.38-1.50 (1H, m), 1.80-2.06 (3H, m), 2.60-3.00 (3H, m), 2.70 (3H, s), 2 ,87

(3H, s), 3.96 (2H, d, J = 4.0 Hz), 4.27 (2H, d, J = 6.0 Hz), 4.85-4.95 (1H, m) , 5.98 (1H, t, J = 6.0 Hz), 6.14 (1H, d, J = 4.0 Hz), 6.55 (1H, d, J = 7.6 Hz), 6 .80-7.16 (6H, m) ppm.

d 1.25 (3H, t, J = 7.0 Hz), 1.40-1.60 (1H, m), 1.85-2.20 (3H, m), 2.04 (3H, s ),

2.45 (2H, t, J = 6.27 Hz), 2.65-3.10 (3H, m), 3.30-3.50 (2H, m), 4.00-4.20 ( 4H, m), 4.90-5.00 (1H, m), 5.50-5.70 (2H, m), 6.50-7.20 (7H, m) ppm.

e 1.20-1.45 (1H, m), 1.65-2.05 (3H, m), 1.95 (3H, s), 2.05-2.25 (2H, m), 2 .50-3.00 (3H, m), 3.00-3.20 (2H, m), 3.85-4.05 (2H, m), 4.65-4.90 (1H, m) , 5.80-6.20 (1H, br s), 6.40-7.20 (9H, m) ppm.

Example 29

In vitro biological characterization

The compounds according to the invention are selective agonists on the V2 receptor. In standard radioligand displacement assays, all compounds give Kj values below 10 µM for the V2 receptor.

Example 30

In vivo biological characterization

The Brattleboro rat is a well-known model of vasopressin deficiency (for a review, see FD Grant, "Genetic models of vasopressin deficiency", Exp. Phvsiol. 85, 203S-209S, 2000). The animals do not excrete vasopressin, and consequently produce large volumes of dilute urine. The compounds of the present invention were administered to Brattleboro rats (0.1-10 mg/kg p.o. in methylcellulose). Urine was collected every hour and the volumes were compared with control animals. The animals had free access to feed and water throughout the experiment. Representative results are given in the table. Results for desmopressin are given for comparison.

Example 31

Pharmaceutical composition for tablet

Tablets containing 100 mg of the compound of Example 5 as the active ingredient were prepared using the following ingredients:

The materials were mixed and then pressed into 2000 250 mg tablets, each containing 100 mg of the compound of Example 5.

The preceding examples show that compounds according to the invention can easily be prepared using standard chemical techniques, and that these compounds have the biological properties that can be expected from V2 receptor agonists. In particular, the compounds are potent antidiuretics in an animal model of vasopressin deficiency. It is thus clear that they can be used in the treatment of human diseases which can currently be treated with desmopressin, for example central diabetes insipidus, nocturnal enuresis and nocturia. It has also been suggested that antidiuretics such as desmopressin can also be used for certain types of urinary incontinence. Such arguments can also be used for compounds according to the present invention.

Desmopressin is also used in the treatment of certain clotting disorders. There is much evidence that this effect is also controlled via the VV receptor (see for example JE Kaufmann et al., "Vasopressin-induced von Willebrand factor from endothelial cells involves V2 receptors and cAMP", J. Clin. Invest. 106, 107- 116, 2000; A Bernat et al., "V2 receptor antagonism of DDAVP-induced release of hemostasis factors in conscious dogs", J. Pharmacol. Ex<p>. Ther. 282. 597-602, 1997), and it may thus it is expected that the compounds according to the present invention can also be used as pro-coagulants.

The scope of the invention is further defined by means of the subsequent claim.

Claims (17)

1. Connection, characterized by the general formula 1, or one of its pharmaceutically acceptable salts; where: V is a covalent bond or NH, X is selected from CH2, O and N-(Ci-C6)alkyl, Z is either S or -CH=CH-, R<1> and R<2> are independent of each selected from H, F, Cl, Br and (Ci-Ce)alkyl, R<3> is selected from OH, O-alkyl and NR<4>R5, R<4> and R<5> are independent of each other H or (C 1 -C 6 )alkyl, or together is -(CH 2 )q-, p is 0, 1, 2, 3 or 4, and q is 4 or 5. 2. Compound or salt according to claim 1, characterized by atZer -CH=CH-. 3. Compound or salt according to claim 1, characterized by atZerS. 4. Compound or salt according to any one of the preceding claims, characterized in that X is CH2. 5. Compound or salt according to any one of the preceding claims, characterized in that R1 is H and R2 is selected from methyl and Cl. 6. Compound or salt according to any one of claims 1 to 4, characterized in that R1 is selected from methyl and Cl, and R2 is H. 7. Compound or salt according to any one of the preceding claims, characterized in that R 3 is O-(C 1 -C 6 )alkyl. 8. Connection according to claim 1, characterized by being selected from l-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-( 4-[N-(2-methoxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-hydroxy- 2-oxoethanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1 -benzazepine, 1 -(4- [N-(5 -methoxy-5 -oxopentanoyl)aminomethyl] -3 - methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5- tetrahydro-1 H-1 -benzazepine, l-(4-[N-(2-hydroxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(3-methyl-4-[N-(2-methylamino-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4,5-tetrahydro- IH- l -benzazepine, l-(4-[N- (2-dimethylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(2-methoxy-2-oxoethylcarbamoyl )aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-amino-2-oxoethylca rbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine, 4-(3-chloro-4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl -5,6,7,8-tetrahydro-4//-thieno [3,2-6]azepine, 5-(4-[N-(4-methoxy-4-oxobutanoyl)aminomethyl]benzoyl)-2,3 ,4,5-tetrahydro-1,5-benzoxazepine, 1 -(4- [N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl] -3 -methylbenzoyl)-5 - methyl-2,3,4,5- tetrahydro-l/f-1,5-benzodiazepine, 1 -(4- [N-(3 -methoxy-3 -oxopropanoyl)aminomethyl] -3 -methylbenzoyl)-2,3,4,5 - tetrahydro-1 H-1 - benzazepine, 1 -(4- [N-(3 -ethoxy-3 -oxopropanoyl)aminomethyl] -3 -methylbenzoyl)-2,3,4,5-tetrahydro- 1 H-1 -benzazepine, l-(4-[ N-(3-hydroxy-3-oxopropanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1 H-1 -benzazepine, 1 -(4- [N-(4-hydroxy-4 -oxobutanoyl)aminomethyl] -3 -methylbenzoyl)-2,3,4,5 - tetrahydro- \ H -\ -benzazepine, 1 -(4- [N-(5 -hydroxy-5 -oxobutanoyl)aminomethyl] -3 - methylbenzoyl)-2,3,4,5-tetrahydro-\H-\-benzazepine, 1-(4-[N-(3-methoxy-3-oxopropanoyl)aminomethyl]-3-niethylbenzoyl)-2,3, 4,5-tetrahydro-1H-1-benzazepine, l-(4-[N'-ethoxycarbonylcarbamoyl)aniinomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1 -benzazepine, l- (4-[N-(2-ethoxy-2-oxoethylcarbamoyl)aminomethyl]-2-methylbenzoyl-2,3,4,5-tetrahydro-1 H-1 -benzazepine, l-(4-[N-(2- isopropoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(4-[N-(2-?er/-butoxy-2-oxoethylcarbamoyl) aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine, l-(3-chloro-4-[N-(2-dimethylamino-2-oxoethylcarbanoyl)aminomethyl]benzoyl )-2,3,4,5-tetrahydro-1H-1-benzazepine, 1-(3-methyl-4-[N-(2-(1-piperidino)-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2, 3,4,5-tetrahydro-1 H-1 - benzazepine, l-(3-methyl-4-[N-(2-(l-pyrrolidino)-2-oxoethylcarbamoyl)aminomethyl]benzoyl)-2,3,4 ,5-tetrahydro-1 H-1 - benzazepine, 1 -(4- [N-(3 -ethoxy-3 -oxopropylcarbamoyl)aminomethyl] -3 -methylbenzoyl)-2,3,4,5 -tetrahydro-1 H- 1 -benzazepine, and 1 -(4-[N-(3-hydroxy-3-oxopropylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetra hydro-IH-l-benzazepine, or a salt thereof. 9. Pharmaceutical composition, characterized by containing an active agent selected from compounds and their pharmaceutically acceptable salts according to any of the preceding claims. 10. Pharmaceutical composition according to claim 9, characterized in that the composition is to be used for the treatment of polyuria. 11. Pharmaceutical composition according to claim 9, characterized in that the composition is to be used for the control of urinary incontinence. 12. Pharmaceutical composition according to claim 9, characterized by the composition being used for "voiding postponement" 13. Pharmaceutical composition according to claim 9, characterized in that the composition is to be used for the treatment of bleeding diseases. 14. Use of a compound according to claim 1 for the preparation of a pharmaceutical preparation for the treatment of nocturnal enuresis, nocturia and diabetes insipidus. 15. Use of a compound according to claim 1 for the production of a pharmaceutical preparation for the control of urinary incontinence. 16. Use according to claim 14, in which it results in voiding postponement. 17. Use of a compound according to claim 1 for the production of a pharmaceutical preparation for the treatment of bleeding diseases.